Mechanisms of commensal bacteria induced humoral immunity

项目概要/摘要 微生物组影响人类健康的许多方面，并与以下疾病有关 肥胖、炎症性肠病、糖尿病和过敏。宿主与共生体之间的平衡 大多数健康人体内的细菌都保持良好。有助于肠道的一种宿主因素 体内平衡是 IgA 亚类的抗体。产生 IgA 的浆细胞存在于粘膜组织中，例如 作为肠道固有层，但它们也可以在包括骨髓在内的全身部位找到。 然而，只有在某些细菌群存在的情况下才会发现骨髓 IgA 水平较高。 骨髓 IgA 分泌浆细胞频率增加与浓度增加相关 血清 IgA 已被证明在多种微生物传播的脓毒症模型中具有保护作用。的 细菌诱导全身 IgA 反应的机制尚不清楚。该提案的主要目标是 采取公正的方法来定义共生细菌用来诱导的基因水平机制 全身性 IgA。此外，我们将研究物种间相互作用如何促进系统性 IgA 特异性。 总之，该提案将为理解全身性抗体反应如何提供一个框架 响应共生细菌而诱导。这种理解可能会带来针对以下疾病的新疗法： 维持肠道稳态或使用共生细菌作为疫苗输送系统。这个提议 将支持我们研究计划的总体愿景，以了解界面上复杂的相互作用 通过破译细菌用于诱导 IgA 反应的基因水平机制来研究细菌和宿主。

Project Summary/Abstract The microbiome affects many aspects of human health and has been linked to diseases such as obesity, inflammatory bowel disease, diabetes, and allergy. The balance between host and commensal bacteria is well maintained in most healthy individuals. One host factor that contributes to intestinal homeostasis is antibody of the IgA subclass. Plasma cells that produce IgA are found in mucosal tissues such as the lamina propria of the gut, but they can also be found in systemic sites including the bone marrow. However, high levels of bone marrow IgA are only found in the presence of certain consortia of bacteria. Increased frequencies of bone marrow IgA-secreting plasma cells are associated with increased concentration of serum IgA that has been shown to be protective in a sepsis model of polymicrobial dissemination. The mechanisms by which bacteria induce systemic IgA responses are unknown. The main goal of this proposal is to take an unbiased approach to defining gene-level mechanisms used by commensal bacteria to induce systemic IgA. Additionally, we will examine how inter-species interactions contribute to systemic IgA specificity. Together, this proposal will provide a framework for understanding how systemic antibody responses are induced in response to commensal bacteria. This understanding could lead to novel therapies aimed at maintaining intestinal homeostasis or using commensal bacteria as a vaccine delivery system. This proposal will support the overall vision of our research program to understand the complex interplay at the interface of bacteria and host by deciphering gene-level mechanisms used by bacteria to induce IgA responses.